Novel extensions of the tert-amino effect: synthesis of azecine- and oxazonine-fused ring systems

The term 'tert-amino effect' was first used by Meth-Cohn and Suschitzky in 1972, to describe unusual cyclizations of ortho -substituted tert-anilines, due to an increased reactivity. In a special subtype of tert-amino effect type 2 reactions a new C-C bond is formed between the α carbon of the tert-aniline group and the β atom of an ortho-vinyl substituent, resulting in the formation of a tetrahydropyridine ring. Type 2 cyclizations have been widely used for the synthesis of various fused ring systems, but only rarely for the synthesis of medium-sized rings or macrocycles.;In the course of my PhD work, I took part in tert-amino effect related studies. We studied potential extensions of the tert -amino effect to bi- and triaryl systems and via type 2 cyclizations novel oxazonine- and azecine-fused ring systems were synthesized. In the applied model compounds, the interacting vinyl and tert-amino moieties were in ortho-ortho'/ortho" positions on two different aromatic rings, connected via a third benzene or pyridazinone ring or an oxygen bridge. The aldehyde intermediates used for the synthesis of vinyl starting compounds were prepared by the reaction of the appropriate sec-aminophenol and 2-fluorobenzaldehyde or via two subsequent Suzuki-couplings from dihalo starting compounds with ortho-sec-aminoand 2-formylphenyl boronic acids. The structures of several intermediates were determined by X-ray diffraction. Cyclization of non-conjugated biaryl ethers demonstrate, that tert -amino effect could operate also via direct hydride transfer, therefore, this type of reaction might be of a broader significance.;As a part of the ongoing vascular-adhesion protein-1 (VAP-1) research program in the Department of Organic Chemistry, starting from some of the intermediates used for tert-amino effect related studies and further biaryl aldehydes, potentially VAP-1 inhibitor derivatives were prepared.